AU2579699A

AU2579699A - Enhancing the toxicity of warfarin in rodents

Info

Publication number: AU2579699A
Application number: AU25796/99A
Authority: AU
Inventors: Richard M. Poche
Original assignee: Reckitt Benckiser LLC
Current assignee: Reckitt Benckiser LLC
Priority date: 1998-03-09
Filing date: 1999-02-03
Publication date: 1999-09-27
Also published as: CA2323433A1; AR018310A1; US6248730B1; WO1999045778A1; EP1061801A1; US20010041737A1; ZA991614B; CN1292642A; BR9908601A

Description

WO 99/45778 PCT/US99/02334 ENHANCING THE TOXICITY OF WARFARIN IN RODENTS This invention relates to methods for enhancing the toxicity of warfarin in rodenticidal compositions and to warfarin-containing rodenticidal compositions which are effective against warfarin-resistant rodents. 5 Warfarin, 3-a-phenylB--acetylethyl-4-hydroxycoumarin, which has the chemical structure

CH

3 I C=O OH I I CH 2 H " O 0 has, since the 1950s been in use as an active ingredient in rodenticidal compositions. In addition to its use as a rodenticide, warfarin is also used, in 10 generally smaller amounts, in humans to provide similar anti-coagulating effects. The basis for the effectiveness of warfarin as a rodenticide lies in the fact that it is effective in small, multiple doses. One or two doses of the compound are seldom fatal if taken at the recommended concentration; thus the 15 hazard of acute toxicity to man, domestic animals, and wildlife is greatly WO 99/45778 PCT/US99/02334 reduced. In practical use, warfarin has been sold as a "concentrate" containing 0.5 percent of the active ingredient. This is diluted for use with a suitable bait, to a concentration of about 0.025 percent. Baits commonly used are cereal products, corn meal, rolled oats, mixed animal feeds, and similar products. 5 Baits containing warfarin can be placed in stations and left there for considerable periods of time, so that the rodent populations may partake of several doses in sequence. Usually the rodents begin to die after four or five daily doses of the materials, and the population is greatly reduced or eradicated in approximately three weeks. Death is caused by hemorrhages, brought about 10 by the action of the warfarin in reducing the clotting power of the blood. These hemorrhages may be external or internal and can be initiated by very slight injury or capillary damage. One of the other advantages of warfarin is that, because multiple ingestions are required to kill the rodents, they do not develop bait shyness. 15 Beginning in 1969, rodents -- particularly rats and, to a somewhat lesser extent, mice -- began showing resistance to warfarin baits. The general assumption was that such resistance had a genetic basis. Similar resistance was found regarding the use of warfarin as an anti-coagulant in treating humans and, to a certain extent, a possible genetic, or at least familial, basis for the 2 0 decrease in effectiveness of warfarin in treating humans has been substantiated. As far as warfarin in rodenticides is concerned, the development of resistance has spawned the search for other rodenticidal compounds, including -2- WO 99/45778 PCT/US99/02334 particularly other coumarin derivatives such as flocoumafen, difenacoum and brodifacoum. Brodifacoum currently appears to be the compound of choice in rodenticidal compositions, although others are used. Unfortunately, many of these other compounds also exhibit toxicity toward household pets and 5 therefore use of brodifacoum-containing rodenticidal compositions has to be carefully controlled in a household environment. As noted above, warfarin, which is often referred to as a "first generation anti-coagulant rodenticide", has the advantage of very low toxicity toward household pets and wildlife and its use does not involve the need to take 10 excessive precautions to avoid contact with household pets or wildlife. Since warfarin has been available for over 40 years and there have been extensive studies of its effectiveness and toxicological properties, it would be extremely advantageous to be able again to use warfarin in commercial rodenticide formulations. 15 It has now been discovered that the efficacy of warfarin in rodenticidal compositions can be enhanced by adding an antibiotic to the warfarin-containing composition. A wide range of antibiotics may be used in the practice of this invention and the choice of antibiotic will depend on various factors including availability, cost, etc. Obviously, the antibiotic chosen should 20 be one whose anti-bacterial effectiveness is not weakened by warfarin. An example of an appropriate antibiotic is tetracycline, or one of its salts or one of -3- WO 99/45778 PCT/US99/02334 its derivatives, and the antibiotic should be added in sufficient amount to inhibit the action of bacteria present in the gastrointestinal tract of the rodent. Accordingly, this invention provides a rodenticidal composition which comprises a rodenticidally effective amount of warfarin and an antibiotic 5 in sufficient amount to inhibit the action of bacteria present in the gastrointestinal tract of the rodent. The antibiotic may be tetracycline, or one of its salts or a derivative thereof. In these compositions, only a relatively small amount of antibiotic is required, generally ranging from about 0.05% to 1.0% based on the weight of the bait. 10 The invention further provides a method for killing rodents, particularly rats and mice, by causing the rodents to ingest a composition containing a rodenticidally effective amount of warfarin and an antibiotic in an amount sufficient to inhibit the action of bacteria present in the gastrointestinal tract of said rodent. The antibiotic may be tetracycline, or one of its salts or 15 derivatives, or others such as cotrimoxazole, metronidazole, erythromycin, fluconazole, isoniazid, miconazole, ciprofloxacin, and itraconazole. Without wishing to be bound by any scientific theory, it is believed that warfarin "resistance" in rodents may not be true resistance, but rather the result of bacterial action which rapidly metabolizes the warfarin so that the 2 0 substance no longer acts against the rodents in its customary manner. Reducing the number of bacteria present also significantly reduces the amount of vitamin -4- WO 99/45778 PCT/US99/02334 K available to the rodent. (Vitamin K is an antidote for warfarin.) Thus, the addition of a small amount of an antibiotic agent to the rodenticidal composition has the effect of substantially inhibiting the action of such bacteria, thereby allowing warfarin to metabolize in its usual manner and act as an 5 effective rodenticide. It is therefore not necessary to kill off all of the bacteria which act against warfarin, but only to inhibit such action for sufficient time to enable the warfarin to metabolize normally. Thus, the amount of antibiotic required in the bait composition need only be in the range of, for example, from about 0.05% to 1.0% by weight of the bait compositions. Warfarin used at a 10 level of 0.005-0.05% in said bait compositions is usually sufficiently effective in controlling rodents. Any antibiotic which acts against the warfarin-inhibiting bacteria is suitable for use in the practice of this invention. These include the well known tricyclic and tetracyclic antibiotics such as tetracycline, its salts and derivatives, 15 for example, tetracycline hydrochloride. Other usable antibiotics include cotrimoxazole, metronidazole, erythromycin, fluconazole, isoniazid, miconazole, itraconazole and ciprofloxacin, as well as their salts and derivatives. The choice of the antibiotic to be used will depend on various factors, including compatibility with other ingredients in the rodenticidal 2 0 composition, stability, cost, palatability toward the target species, etc. The choice of the particular antibiotic to be employed is well within the knowledge of persons skilled in the art. 5- WO 99/45778 PCT/US99/02334 Warfarin-containing rodenticidal compositions are typically formulated as granular bait compositions containing from 50-300 ppm, preferably about 250 ppm, of warfarin. The amount of antibiotic to be added to such composition should be from about 0.005 to 0.05% by weight of the 5 warfarin. The bait is typically formulated with from 0.5% to 2.5% of warfarin concentrate in a suitable binder such as corn oil. If corn oil is used as a binder, it can be present in an amount of from about 0.5% to about 2% of the total composition. The binder and warfarin are then mixed in with a grain-based bait composition of the type known in the art. Prior to mixing the composition, an 10 appropriate amount of an antibiotic, such as tetracycline hydrochloride, is added. In addition, an antioxidant may be added to the composition as a preservative for both the warfarin and the antibiotic. The compositions of this invention may be used for a variety of rodent control products to reduce the population of house mice, rats, field mice, 15 ground squirrels, and other rodents which may be of concern to public health. Example I A typical formulation has the following constituents: Ingredient % Grain carrier 93.9 Corn oil 1.0 Warfarin Concentrate (0.5%) 5.0 Tetracycline hydrochloride 0.1 Total 100.0 -6- WO 99/45778 PCT/US99/02334 Example II A formulation similar to Example I containing 50 ppm warfarin was tested on groups of warfarin-resistant Norway rats from Chicago, Illinois, and compared against similar formulations without antibiotic. Each group tested 5 had 10 animals. The results are shown in the following table, which contains mortality figures after 5 days of feeding. Group Tetracycline Mortality 1 Yes 9/10 2 No 5/10 The presence of the antibiotic tetracycline hydrochloride appears to enhance the toxicity of warfarin. Example III 10 Formulations similar to that of Example I containing tetracycline or metronidazole were tested on groups of Norway rats believed to be warfarin resistant. Each group tested consisting of 8 animals, 4 males and 4 females. Control groups were fed a formulation containing no antibiotic. Other groups were fed formulations containing tetracycline at a concentration of 0.1% (as in 15 Example I) or metronidazole at the same concentration. The test animals were exposed to the warfarin-containing bait for 6 days and observed for another 10-day period. The results are shown in the -7- WO 99/45778 PCT/US99/02334 following table. The column headed "Average Kill Time" is the average number of days which the dead rats survived before dying. Average Kill Group Antibiotic Mortality Time 3 none 5/8 6.1 4 tetracycline 7/8 6.9 5 metronidazole 7/8 7.3 6 none 5/8 6.7 7 tetracycline 7/8 7.0 8 metronidazole 8/8 6.4 In addition to the enhanced mortality rates, these data show that the average kill time is not appreciably affected. The fact that the average kill time is not 5 reduced is advantageous in that the addition of antibiotic to the warfarin formulation is not likely to lead to bait shyness among the surviving animals. -8-

Claims

1. A method of enhancing the efficacy of warfarin in a rodenticide which comprises adding an antibiotic to a warfarin-containing rodenticidal composition.

2. A method according to claim 1 wherein the antibiotic is added in sufficient amount to inhibit the action of bacteria present in the gastrointestinal tract of a rodent.

3. A method according to claims 1 or 2 wherein the antibiotic is tetracycline, cotrimoxazole, metronidazole, erythromycin, fluconazole, isoniazid, miconazole, ciprofloxacin, itraconazole, or a salt or derivative thereof.

4. A method according to claim 3 wherein the antibiotic is tetracycline or a salt or a derivative thereof.

5. A method according to claim 4 in which the antibiotic is tetracycline or a salt thereof.

6. A method according to claim 3 in which the antibiotic is metronidazole.

7. A method for killing rodents which comprises causing the rodents to ingest a composition comprising a rodenticidally effective amount of -9- WO 99/45778 PCT/US99/02334 warfarin and an antibiotic in an amount sufficient to inhibit the action of bacteria present and to reduce the amount of vitamin K in the gastrointestinal tract of said rodents.

8. A method according to claim 7 in which the antibiotic is tetracycline, cotrimoxazole, metronidazole, erythromycin, fluconazole, isoniazid, miconazole, ciprofloxacin, itraconazole, or a salt or derivative thereof.

9. A method according to claim 8 in which the antibiotic is tetracycline or a salt or a derivative thereof.

10. A method according to claim 9 in which the antibiotic is tetracycline or a salt thereof.

11. A method according to claim 8 in which the antibiotic is metronidazole.

12. A composition for killing rodents comprising a rodenticidally effective amount of warfarin and an antibiotic in sufficient amount to inhibit the action of bacteria present in the gastrointestinal tract of the rodent.

13. A composition according to claim 12 in which the antibiotic is tetracycline, cotrimoxazole, metronidazole, erythromycin, fluconazole, - 10- WO 99/45778 PCT/US99/02334 isoniazid, miconazole, ciprofloxacin, itraconazole, or a salt or derivative thereof.

14. A composition according to claim 13 in which the antibiotic is tetracycline or a salt or derivative thereof

15. A composition according to claim 14 in which the antibiotic is tetracycline or a salt thereof.

16. A composition according to claim 13 in which the antibiotic is metronidazole.

17. A composition according to claim 13 in which said composition comprises warfarin and the antibiotic suspended in a solid carrier.

18. A composition according to claim 17 in which the antibiotic is present in an amount of from about 0.05 to 1.0% based on the weight of the composition.

19. A composition according to claim 18 in which warfarin is present in an amount of from about 50 to about 300 ppm. G:\USERS\ANP\FR\08295\305001 ,305\ o l \PATAPP2.doc -11-